Nature Medicine, 2019-01, Vol.25 (1), p.152-164
2019
Details
- Autor(en) / Beteiligte
- Titel
- Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
- Ist Teil von
- Nature Medicine, 2019-01, Vol.25 (1), p.152-164
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-8956, 1546-170XeISSN: 1546-170X, 1744-7933DOI: 10.1038/s41591-018-0223-3Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_139975160
- Format
- –
- Schlagworte
- Analysis, Animals, Brain, Cell Death, Cell Death - genetics, Dementia, Dementia - genetics, Dementia disorders, Disease Models, Animal, Drug discovery, Epidemiology, Evolution, Molecular, Frontotemporal Dementia, Frontotemporal Dementia - genetics, Frontotemporal Dementia - pathology, Gene expression, Gene Expression Regulation, Gene Regulatory Networks, Genes, Genetic diversity, Genetic Predisposition to Disease, Genetic Vectors, Genetic Vectors - metabolism, Humans, Life Sciences, Medical schools, Medicin och hälsovetenskap, Messenger RNA, Mice, Inbred C57BL, Mice, Transgenic, MicroRNA, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, Modules, Mutation, Neurodegeneration, Neurodegenerative Diseases, Neurodegenerative Diseases - genetics, Neurons, Neurophysiology, Proteomics, Reproducibility of Results, Ribonucleic acid, RNA, RNA, Messenger, RNA, Messenger - genetics, RNA, Messenger - metabolism, tau Proteins, tau Proteins - metabolism, Transcriptome, Transcriptome - genetics